Role of Cell Cycle Biomarkers in Human Papillomavirus Related Uterine Lesions

Cervical cancer (CC) is caused by a persistent infection by certain human papillomavirus (HPV) genotypes. Although Papanicolaou (Pap) Test is considered the most cost-effective test for reducing CC mortality, a considerable number of high-grade precursor lesions of CC could pass unnoticed with the Pap. The addition of high-risk human papillomavirus (HPV) genotype detection in cervical cytology has improved the sensitivity, but due to its low specificity, further biomarkers of malignancy have been searched for. Given the fact that the oncogenic role of HPV is exerted primarily by affecting cell cycle control it is not surprising that most of the useful biomarkers of HPV-related uterine lesions are cell cycle proteins, with p16 and Ki67 the most widely used. More recently, molecular profiling and marker combination tests have identified the utility of antibody cocktails such as p16/Ki67 dual and ProEx C, which detect both TOP2A and MCM2 cell cycle proteins. In this article we revise the rationale for the use of the most common cell cycle biomarkers, also including p53 and cyclin D1, and their clinical utility drawing attention to novel biomarkers and how HPV vaccination could influence their use.